Category: Methodology

Some Medical Researchers Seek Patient Input on Execution of Studies

In the story quoted below some medical researchers are seeking patient involvement in studies, but I was disappointed to realize that the involvement is mostly superficial with the aim of getting patient agreement to be part of the study. The researchers in the story still see a big divide between patients and doctors. Doctors see patterns and create hypotheses to be tested. Patients, if they want, can stand by posters, and make minor suggestions on the execution of study design.

I suggest, more ambitiously, that patients sometimes, if allowed, can see patterns and create hypotheses. They have the incentive, the skin in the game. And sometimes they have direct experience on what works and what does not work.

(p. R6) Joel Nowak, a 66-year-old Brooklyn, N.Y., resident with metastatic prostate cancer, knows a lot about cancer research. Over the years, he has contributed blood, saliva and medical information to studies in hopes of helping investigators battle the disease.

But something has nagged at him. Almost always, Mr. Nowak says, investigators want data, “but you never hear from them again.”

Then he was asked to join a new endeavor that is trying to change that—by making participants into partners.

The Metastatic Prostate Cancer Project, launched by the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute in Boston, is trying to give participants a bigger stake in studies by asking them for input, inviting them to events and keeping them updated on progress.

. . .

Patients are . . . invited for a tour of the Broad Institute to see its gene-sequencing machines or to meet and share ideas with researchers, says Nikhil Wagle, director of the umbrella initiative.

Dr. Wagle thinks the approach has led to unusually fast and large enrollment. More than 4,000 people enrolled in the breast-cancer project and over 290 in the angiosarcoma initiative. In just a few weeks, more than 200 signed up for the prostate-cancer study.

. . .

Keeping participants up-to-date is another concern for researchers. It is an issue close to home for Corrie Painter, principal investigator of the angiosarcoma project at the Broad and one of the creators of all three of the institute’s cancer initiatives.

Dr. Painter draws on her experiences as a cancer survivor and research participant in shaping interactions with patients. She was diagnosed with angiosarcoma nearly eight years ago. Dr. Painter says that after her diagnosis, like many patients, she felt frustrated at being treated more “as passive recipients of care rather than part of the process of discovery.”

. . .

Meanwhile, some patients are taking the opportunity to play a larger role in shaping studies. Mr. Nowak, for one, joined a patient advisory council of the prostate-cancer project. Members communicate on videoconferences, email exchanges and in person. During a meeting at the Broad, researchers showed a prototype for the saliva kits that were going to be mailed to patients to collect samples.

The advocates told researchers to take “Metastatic Prostate Cancer Project” off the box. “There are a lot of men who don’t want other people to know they have cancer,” says Mr. Nowak.

For the full story see:

Amy Dockser Marcus. “Researchers Look to Enlist Patients as Partners.” The Wall Street Journal (Monday, Feb. 25, 2018 [sic]): R6.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 25, 2018 [sic], and has the title “Medical Researchers Look to Enlist Patients as Partners.” The last two ellipses above indicate where I omit sentences that appeared in the longer online version, but not in the print version.)

Marcus’s story is related to her book:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Large Medical Databases Would Allow Discovery and Testing of Causal Patterns of Diseases

After considerable effort, as of the writing of the article quoted below, Dr. Wagle has only been able to gather data on 375 of the roughly 155,000 metastatic breast cancer patients in the U.S. Many have long complained about the difficulty in obtaining and consolidating medical records. Exploring the reasons would take a longer article than the one quoted below. Part of the story is the Health Insurance Portability and Accountability Act of 1996 (HIPAA). It was passed to protect patient privacy, but it served as cover for medical institutions to stonewall patients, policy makers, and other medical institutions from obtaining information. The institutions make the process of obtaining medical information as slow, opaque, and onerous as possible. Partly this is a result of the general inefficiency of medical bureaucracy. Regulations limit competition among medical institutions and limit entrepreneurship, allowing inefficiencies to persist. To those who are mission-oriented within the bureaucracy, providing records may seem a lower priority than issues affecting current medical care. But also, restricting information may increase patient lock-in. Ceteris paribus, a patient may choose to stay at an institution that has long health records for the patient. Also, providing less information to third parties may make the institution less vulnerable to criticism and law suits.

Ideally, Dr. Wagle’s database would serve as a modern day version of the dusty hospital archives that Dr. William Coley pursued to find a pattern among the patients who had been spontaneously cured of their cancer in the late 1800s.

From personal experience I can say that getting patient information is easier now than it was 30 years ago, at least for the patient to obtain their own information.

An important side point is Dr. Wagle’s emphasis on the value of obtaining patient narratives, in addition to coded data. Narratives allow the discovery of additional causes or effects, beyond what the initial coders include in the coded data. Gary Klein makes this point in defending the value of what he calls “stories” (Klein 2017).

(p. D4) Dr. Nikhil Wagle thought he had a brilliant idea to advance research and patient care.

Dr. Wagle, an oncologist at the Dana Farber Cancer Institute in Boston, and his colleagues would build a huge database that linked cancer patients’ medical records, treatments and outcomes with their genetic backgrounds and the genetics of their tumors.

The database would also include patients’ own experiences. How ill did they feel with the treatments? What was their quality of life? The database would find patterns that would tell doctors what treatment was best for each patient and what patients might expect.

The holdup, he thought, would be finding patients. Instead, the real impediment turned out to be gathering their medical records.

. . .

Dr. Wagle is making data from medical records and patients’ experiences public as he gets them. After 2 1/2 years, though, he is disappointed by how little there is to share.

The patient who inspired his project had a lethal form of thyroid cancer. She was expected to die in a few months. In desperation, doctors gave her a drug that by all accounts should not have helped.

To everyone’s surprise, her tumors shrank to almost nothing, and she survived. She was an “extraordinary responder.”

Why? It turned out that her tumor had an unusual mutation that made it vulnerable to the drug.

And that got Dr. Wagle thinking. What if researchers had a database that would allow them to find these lucky patients, examine their tumors, and discover genetic mutations that predict which drugs will work?

. . .

Dr. Wagle decided to build a database, starting with metastatic breast cancer, his specialty. There are about 155,000 metastatic breast cancer patients in the United States. He would use social media, online forums and advocacy groups to reach out to patients for their records.

. . .

Startlingly, faxing “is the standard,” Ms. McGillicuddy said, for medical records requests.

The process can be frustrating. Fax numbers can be out of date. Some medical centers will not accept electronic patient signatures on the permission forms.

Sometimes, the medical centers just ignore the request — and the second request. In the end, Ms. McGillicuddy said, the project gets fewer than half the records it requests.

Then comes the laborious task of extracting medical information from the records and entering it into the database. A faxed medical record may be 100 or 200 pages long.

So far, the breast cancer project has received 450 records for 375 patients. (Each patient tends to have more than one record, because the women typically are seen at more than one medical center.)

For the full story see:

Gina Kolata. “Concealing New Cancer Treatments.” The New York Times (Tuesday, May 22, 2018 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date May 21, 2018 [sic], and has the title “New Cancer Treatments Lie Hidden Under Mountains of Paperwork.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.

When Free People Do Not Volunteer for Clinical Trials, Should Researchers Recruit Prisoners?

On the issue of how to ethically motivate prisoners to volunteer for clinical trails on the efficacy of salt-restricted diets, why not offer wages to the prisoners? Prisoners are already sometimes paid small amounts for other activities, like making license plates. Better yet, take my suggestion with a grain of salt, and settle the dispute with well-done observational studies.

(p. D3) Suppose you wanted to do a study of diet and nutrition, with thousands of participants randomly assigned to follow one meal plan or another for years as their health was monitored?

In the real world, studies like these are nearly impossible. That’s why there remain so many unanswered questions about what’s best for people to eat. And one of the biggest of those mysteries concerns salt and its relationship to health.

But now a group of eminent researchers, including the former head of the Food and Drug Administration, has suggested a way to resolve science’s so-called salt wars. They want to conduct an immense trial of salt intake with incarcerated inmates, whose diets could be tightly controlled.

The researchers, who recently proposed the idea in the journal Hypertension, say they are not only completely serious — they are optimistic it will happen.

. . .

Dr. Daniel W. Jones, a professor of medicine and physiology at the University of Mississippi School of Medicine and former president of the American Heart Association, was alarmed by the bitter arguments and increasingly personal disputes between researchers who disagree about salt.

So he invited senior medical scientists on both sides of the debate to meet in Jackson, Miss., to figure out how to settle their differences.

. . .

So suppose you do the study in prisons, said Dr. Jones. Is the research supposed to benefit the prisoners or just the population in general? If the prisoners would not benefit, the study would be unethical.

People who are not incarcerated can choose how much sodium they consume, but prisoners cannot — they eat whatever the facility provides. If there is uncertainty about the ideal amount of sodium, the experts concluded, prisoners would benefit from a study that settled the matter.

. . .

Dr. Macklin, in a telephone interview, also said many prisoners would be happy to jump in. She has taught in a maximum security facility and has studied the ethics of doing research in prisons.

“They would say they want to give back to society,” Dr. Macklin said.

. . .

Prison administrators have told Dr. Jones they would be willing to consider a proposal for a randomized trial of salt.

For the full story see:

Gina Kolata. “Looking to Prison for a Health Study.” The New York Times (Tuesday, June 5, 2018 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date June 4, 2018 [sic], and has the title “The Ideal Subjects for a Salt Study? Maybe Prisoners.”)

The academic article co-authored by Dr. Jones that proposes a randomized double-blind clinical trial (RCT) in prisons is:

Jones, Daniel W., Friedrich C. Luft, Paul K. Whelton, Michael H. Alderman, John E. Hall, Eric D. Peterson, Robert M. Califf, and David A. McCarron. “Can We End the Salt Wars with a Randomized Clinical Trial in a Controlled Environment?” Hypertension 72, no. 1 (July 2018): 10-11.

If Immortality Does Not Violate the Laws of Physics, Entrepreneurs Can Achieve It

The late Nobel-Prize-winning physicist and idiosyncratic Richard Feynman also said something similar to the quote attributed to Arram Sabeti below.

I do not believe that Feynman was explicitly named, or had any lines, in the movie “Opennheimer,” but you can see his character in the background of one scene playing the bongo drums. Perhaps he was eccentric, but I liked his views on methodology and his unpretentious, optimistic, and straightforward spirit.

(p. 9) As the longevity entrepreneur Arram Sabeti told The New Yorker: “The proposition that we can live forever is obvious. It doesn’t violate the laws of physics, so we can achieve it.”

For the full commentary see:

Dara Horn. “The Men Who Want to Live Forever.” The New York Times, SundayReview Section (Sunday, January 28, 2018 [sic]): 9.

(Note: the online version of the commentary has the date Jan. 25, 2018 [sic], and has the same title as the print version.)

Bacteria Can Be Genetically Reprogrammed to Cure Cancer Tumors in Mice

Reprograming bacteria to cure cancer tumors is a novel and plausible approach, but there are many other novel and plausible approaches. Cancer is a complicated and diverse disease; maybe we will eventually see “cancer” as many different diseases. We have too much uncertainty to mandate one centrally planned approach. Plus citizens have the right to keep the money they earn and to choose how to spend that money. We should keep taxation and regulations low so that diverse funders can follow their judgements to fund diverse approaches.

(p. D3) Scientists have used genetically reprogrammed bacteria to destroy tumors in mice. The innovative method one day may lead to cancer therapies that treat the disease more precisely, without the side effects of conventional drugs.

The researchers already are scrambling to develop a commercial treatment, but success in mice does not guarantee that this strategy will work in people. Still, the new study, published on Wednesday in the journal Nature Medicine, is a harbinger of things to come, said Dr. Michael Dougan, an immunologist at Massachusetts General Hospital in Boston.

. . .

Our immune cells can sometimes recognize and destroy cancer cells without assistance. But tumors may hide from the immune system by taking advantage of a gene called CD47.

Normally, the gene makes a protein that studs the surface of red blood cells, a kind of sign that reads, “Don’t Eat Me.” Immune cells see it, and pass by healthy red blood cells.

. . .

In recent years, scientists have been developing antibodies that can attach to CD47 proteins on cancer cells, masking the “Don’t Eat Me” sign. Then the body’s immune cells learn to recognize the cancer cells as dangerous and attack.

. . .

Nicholas Arpaia, an immunologist at Columbia University in New York, and Tal Danino, a synthetic biologist, wondered if they could use bacteria to turn the immune system against cancer cells — but from within tumors, rather than from outside.

. . .

The researchers inserted the nanobody gene into the bacteria, turning them into nanobody factories. Then the team injected five million of the altered microbes into mouse tumors.

The bacteria were also programmed to commit mass suicide. After they established themselves and multiplied, 90 percent of the bacteria ripped themselves apart, spilling out nanobodies. The nanobodies attached to CD47 proteins on the cancer cells, robbing them of their camouflage.

. . .

Dr. Danino co-founded a company, GenCirq, that is exploring using these reprogrammed bacteria to treat cancer. Dr. Arpaia is on the leadership board.

Their goal is to treat some forms of metastatic cancer with a pill of programmed bacteria. In earlier research, Dr. Danino and colleagues showed that bacteria swallowed by mice can reach the liver and invade tumors there.

For the full commentary see:

Carl Zimmer. “Matter; Bacteria, Altered to Destroy Cancer.” The New York Times (Tuesday, July 9, 2019 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the commentary has the date July 3, 2019 [sic], and has the title “Matter; New Weapons Against Cancer: Millions of Bacteria Programmed to Kill.”)

The paper in PLOS Biology co-authored by Thomas Stoeger and mentioned above is:

Chowdhury, Sreyan, Samuel Castro, Courtney Coker, Taylor E. Hinchliffe, Nicholas Arpaia, and Tal Danino. “Programmable Bacteria Induce Durable Tumor Regression and Systemic Antitumor Immunity.” Nature Medicine 25, no. 7 (July 2019): 1057-63.

The Patterns in Unexpected Cancer Cures Can Yield Actionable Insight

The method for fighting cancer discussed by Gina Kolata in the passages quoted below, is similar to the method that led William Coley to first develop immunotherapy in the late 1800s. Coley searched the archives of his hospital, seeking any cases in which cancer seemed to have been spontaneously cured. When he had a few cases he looked for a common feature that might explain the cures. He found that in each case the patient had a severe viral or bacterial infection. When the patient’s immune system cured them of the infection, it also, as a desirable side-effect, cured them of the cancer. In the case of the rare ovarian discussed below, Dr. Levine hypothesizes that the common feature of the rare single-mutation cancers that can be cured by immunotherapy drugs, is that there is a mutated master gene that turns on and off other genes–creating an abnormal variation that somehow alerts the immune system of the presence of tumor cells that should be attacked. (The article quoted below is now over six years old–I wonder if in those six years Dr. Levine has found evidence to support, modify, or reject his hypothesis?) [My memory is foggy on this, but I think Steven Rosenberg may also have applied a similar method after he encountered a case of spontaneous cancer cure when he was working in a veteran’s hospital early in his career–see Rosenberg and Barry, 1992.]

Notice that the four patients only were cured because they had the courage and boldness to ask their oncologist to try a therapy that the standard protocol said would fail. And notice that the four patients only were cured because they had oncologists who had the courage and boldness to violate accepted protocols. Or maybe something besides courage and boldness explains the oncologists’ actions. Maybe the oncologists were practicing medicine in countries were hospitals, regulatory agencies, and health insurance companies did not exert as much pressure to follow the protocol as is exerted in the United States? (I wonder if there is enough information publicly available to check this possibility.)

Notice that instead of searching a dusty archive, Levine joined a patient ovarian cancer Yahoo discussion group. Patients were trying to be in control of their cancers, and unlike some doctors, Levine had the humility to think he could learn from what these activist patients reported. Citizen science is a resource to be used, not a distraction to be tamped down or ridiculed. [Amy Dockser Marcus defends citizen science, and gives an extended example, in her We the Scientists.]

Finally note that the method pursued by Coley and Levine can yield genuine actionable knowledge. Randomized double-blind clinical trials are not the only sources of knowledge.

Gina Kolata has written many thought-provoking articles. I hope to follow-up on this one sometime.

(p. D1) No one expected the four young women to live much longer. They had an extremely rare, aggressive, and fatal form of ovarian cancer. There was no standard treatment.

The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized treatment of cancer. At first, they were told the drugs were out of the question — they would not work against ovarian cancer.

Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.

. . .

“We need to study the people who have a biology that goes against the conventional generalizations.”

Four women hardly constitutes a clinical trial. Still, “it is the exceptions that give you the best insights,” said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.

The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman’s teens or 20s. It is so rare that most oncologists never see a single patient with it.

. . .

(p. D3) Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Dr. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.

The women reported that their tumors shrank immediately.

. . .

Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumors — carry few mutations.

“These are the cancers that rarely respond,” Dr. Pardoll said.

The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fueled by just one genetic mutation, just made no sense.

“For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load,” Dr. Pardoll said.

. . .

And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, was one of them.

She found out she had cancer in December 2011.

. . .

For the next four years, Ms. Sousa’s doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors emerged.

. . .

Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued shrinking as she continued with the drug — so much that her doctors now say she has no evidence of disease. Life has returned to normal.

. . .

What saved her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.

He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognize as abnormal.

Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. “We saw this result and weren’t sure what to make of it,” he said.

Dr. Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune system may recognize that cells in which genes are erratically turning on and off are dangerous and should be destroyed.

“That is strictly hypothesis,” Dr. Levine cautioned.

For the full story see:

Gina Kolata. “Cured Unexpectedly.” The New York Times (Tuesday, February 20, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 19, 2018 [sic], and has the title “Doctors Said Immunotherapy Would Not Cure Her Cancer. They Were Wrong.”)

The academic article co-authored by Dr. Levine that reports on the remission of a rare ovarian cancer in four women is:

Jelinic, Petar, Jacob Ricca, Elke Van Oudenhove, Narciso Olvera, Taha Merghoub, Douglas A. Levine, and Dmitriy Zamarin. “Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade.” Journal of the National Cancer Institute 110, no. 7 (2018): 787-90.

The book by Marcus that I praise above is:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Rosenberg’s encounter with a case of spontaneous cancer cure, that I mention above, can be found somewhere early in:

Rosenberg, Steven A., and John M. Barry. The Transformed Cell: Unlocking the Mysteries of Cancer. New York: G.P. Putnam’s Sons, 1992.

Government Gave “40 Years of Seriously Incorrect Advice” on Trans Fats

The government’s advice often turns out to be wrong. That is an added argument for not giving the government the power to enforce its advice through mandatory regulations. (“Added” to the fundamental argument based the right to free choice.)

[In May 2021 Nicholas Wade, the author of the review quoted below, showed enormous courage in being one of the first few to risk cancelation by presenting a cogent case that Covid leaked from a Wuhan lab.]

(p. C9) Rachel Carson rightly complained in “Silent Spring” that farmers were sloshing far too many harmful pesticides into the environment. But she took aim at the wrong one. DDT, a mild and enormously effective pesticide, helped rid the United States of malaria and its benefits, if more discriminately pursued, could have outweighed its costs.

The overstrict verdict against DDT is an instance of the harms that can ensue when scientific evidence is ignored. This and other cases described by Paul A. Offit in “Pandora’s Lab: Seven Stories of Science Gone Wrong” raise provocative questions about the reasons that science is misused in modern society.

. . .

Another case of medical advice based on insufficient data is that of dietary fat. As Dr. Offit tells the story, in the 1970s the government advised cutting down on fat consumption. In the 1980s the message changed. Unsaturated fats were good; only saturated fats were bad: Eat margarine, not butter. But then it turned out that unsaturated fats came in two forms, known to chemists as “cis” and “trans,” and that “trans fats” were appallingly active promoters of heart disease. Margarine and hydrogenated vegetable cooking oils, whose use had been encouraged, were rich in trans fats. After 40 years of seriously incorrect advice, trans fats were mostly eliminated from the American diet only in 2012.

. . .

Besides his overconfidence in the checking mechanisms of science, Dr. Offit goes too easy on the motives of those who abuse science. Environmentalists, for instance, are interested in achieving political results, not in distracting scientific caveats and uncertainties, which they do their best to suppress. It is their propensity to take everything to excess that leads to obscurantist positions, such as irrational fear of genetically modified crops.

For the full review see:

Nicholas Wade. “A Little Knowledge.” The Wall Street Journal (Saturday, April 8, 2017 [sic]): C9.

(Note: ellipses added.)

(Note: the online version of the review was updated April 7, 2017 [sic], and has the same title as the print version.)

The book under review is:

Offit, Paul A. Pandora’s Lab: Seven Stories of Science Gone Wrong. Washington, D.C.: National Geographic, 2017.

Potential Malaria Breakthrough Drug Forgotten and Now Ignored Due to Its Chemical Relative and Its Venue of Invention

Progress in science, like progress everywhere, is not inevitable. Progress often requires champions or entrepreneurs to persist in overcoming obstacles. In the case of DFDT, the obstacles arise due to the drug’s association with the chemical DDT and with Nazi Germany, the first of which is unjustly reviled and the second of which is justly reviled. But DFDT should not be judged by either its relatives or its venue of origins It should be judged by its efficacy against malaria, and by its effects, if any, on the environment.

(p. D1) In postwar Allied intelligence reports examined by Dr. Ward and his colleagues, German scientists claimed their insecticide, now called DFDT, was more effective than DDT. Allied officials dismissed those assertions as fanciful, especially given the deplorable behavior of Hoechst, the German chemical manufacturer that developed the insecticide, during the war. The company had forced residents of countries occupied by Germany to work in its factories, and it tested drugs on concentration camp prisoners.

The insecticide was forgotten for decades.

Now, work by Dr. Ward and his colleagues, reported this month [Oct. 2019] in an article in the Journal of the American Chemical Society, appears to corroborate the German claims. The forgotten compound killed mosquitoes in as little as one-fourth the time as DDT.

. . .

(p. D4) Conceivably the more lethal DFDT could be used in even smaller, possibly safer doses. A new option could allow public health officials to rotate insecticides and thwart the resistance to DDT in many mosquitoes today.

“It’s exciting and desperately needed,” said Duane J. Gubler, an emeritus professor in the emerging infectious diseases program at Duke University and the National University of Singapore Graduate Medical School. He was not involved in the study.

But will anyone today risk the time and money needed to determine whether DFDT could be a safe and effective tool against malaria as well as other mosquito-borne diseases like Zika, dengue and yellow fever?

“Donors, governments, they just don’t want the backlash, even if it’s not wholly justified,” said Bart Kahr, Dr. Ward’s colleague at N.Y.U. and an author of the paper.

. . .

The N.Y.U. chemists started the research with no interest in insecticides whatsoever.

They were studying materials that crystallize in a twisted helical pattern. One of the ways to identify such molecules is to scan the internet for images of crystals made by hobbyists. DDT, they found, exhibited the characteristic pinwheel gradients of a helical crystal when illuminated with polarized light.

Jingxiang Yang, a postdoctoral researcher at N.Y.U., started growing DDT crystals and found not only the expected crystals but also more jumbled, chaotic patterns.

“There was some organized and some crazy,” Dr. Kahr said. “We didn’t expect the other stuff, and that other stuff turned out to be a different arrangement of molecules in the crystal. That form wasn’t known to science.”

That led to the next set of experiments. “Since we have two forms,” Dr. Kahr said, “it was natural to ask, which of these forms was the historical killer of insects?”

It turned out that the chaotic form of DDT is deadlier.

As they were going through early scientific data on DDT, the N.Y.U. chemists found mentions of DFDT.

The compound, difluoro-diphenyl-trichloro-ethane is the same molecule as DDT, except with fluorine atoms replacing two of the chlorines.

The Germans developed DFDT at least in part to avoid paying the licensing fees for DDT to the Swiss. It is also possible that the chemical ingredients for DFDT, although considerably more expensive at the time than those for DDT, may have been more readily available in wartime Germany.

. . .

Dr. Kahr wonders: If DFDT had displaced DDT, would the 1955 push have succeeded in bringing malaria under control before resistance set in? “What if this compound wasn’t forgotten,” he said. “What would the world be like? Science doesn’t go as linearly as the general public thinks it does.”

For the full story see:

Kenneth Chang. “Old Mix To Fight Malaria?” The New York Times (Tuesday, October 22, 2019 [sic]): D1 & D4.

(Note: ellipses, and bracketed month, added.)

(Note: the online version of the story was updated Oct. 22, 2019 [sic], and has the title “A Nazi Version of DDT Was Forgotten. Could It Help Fight Malaria?” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Ward, Kahr, and others, and mentioned above, is:

Zhu, Xiaolong, Chunhua T. Hu, Jingxiang Yang, Leo A. Joyce, Mengdi Qiu, Michael D. Ward, and Bart Kahr. “Manipulating Solid Forms of Contact Insecticides for Infectious Disease Prevention.” Journal of the American Chemical Society 141, no. 42 (2019): 16858-64.

The Efficacy of Personalized Drugs Designed for Only One Patient Cannot Be Tested by Randomized Double-Blind Clinical Trials (RCTs)

We know that there are times when therapies work for some patients, but not for others. But clinical trials often do not account for such differences. If the effects of the new drug are not widespread enough among the general population, the trial will be deemed a failure, and the F.D.A. will not allow the drug to be taken even by the patients who would have benefitted from it. Maybe the solution is liberty. Allow physicians liberty on what therapies to suggest, and patients liberty on what therapies to try. This especially makes sense when the disease is dire and no effective therapy is yet widely known.

Many predict that we are moving toward personalized medicine. We need less regulation and more liberty so personalized medicine can progress, and more patients can be more quickly cured of more diseases. We need a sense of urgency in requesting liberty.

(p. D3) A new drug, created to treat just one patient, has pushed the bounds of personalized medicine and has raised unexplored regulatory and ethical questions, scientists reported on Wednesday [Oct. 9, 2019].

The drug, described in The New England Journal of Medicine, is believed to be the first “custom” treatment for a genetic disease. It is called milasen, named after the only patient who will ever take it: Mila (mee-lah) Makovec, who lives with her mother, Julia Vitarello, in Longmont, Colo.

. . .

Ms. Vitarello . . . set up Mila’s Miracle Foundation and was appealing for donations on GoFundMe. So, she began fund-raising in earnest, eventually raising $3 million for a variety of research efforts.

Dr. Yu’s team oversaw development of the drug, tested it in rodents, and consulted with the Food and Drug Administration. In January 2018, the agency granted permission to give the drug to Mila. She got her first dose on Jan. 31, 2018.

With continued treatments, the number of seizures has diminished so much that the girl has between none and six a day, and they last less than a minute.

Milasen is believed to be the first drug developed for a single patient (CAR-T cancer therapies, while individualized, are not drugs). But the path forward is not clear, Dr. Yu and his colleagues acknowledged.

. . .

. . . how might a custom drug’s efficacy might be evaluated, and how should regulators weigh the urgency of the patient’s situation and the number of patients who could ultimately be treated.

For the full story see:

Gina Kolata. “Drug Designed for One Raises Many Questions.” The New York Times (Tuesday, October 15, 2019 [sic]): D3.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the story has the date Oct. 9, 2019 [sic], and has the title “Scientists Designed a Drug for Just One Patient. Her Name Is Mila.” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Dr. Yu that reports on the personalized drug milasen is:

Kim, Jinkuk, Chunguang Hu, Christelle Moufawad El Achkar, Lauren E. Black, Julie Douville, Austin Larson, Mary K. Pendergast, Sara F. Goldkind, Eunjung A. Lee, Ashley Kuniholm, Aubrie Soucy, Jai Vaze, Nandkishore R. Belur, Kristina Fredriksen, Iva Stojkovska, Alla Tsytsykova, Myriam Armant, Renata L. DiDonato, Jaejoon Choi, Laura Cornelissen, Luis M. Pereira, Erika F. Augustine, Casie A. Genetti, Kira Dies, Brenda Barton, Lucinda Williams, Benjamin D. Goodlett, Bobbie L. Riley, Amy Pasternak, Emily R. Berry, Kelly A. Pflock, Stephen Chu, Chantal Reed, Kimberly Tyndall, Pankaj B. Agrawal, Alan H. Beggs, P. Ellen Grant, David K. Urion, Richard O. Snyder, Susan E. Waisbren, Annapurna Poduri, Peter J. Park, Al Patterson, Alessandra Biffi, Joseph R. Mazzulli, Olaf Bodamer, Charles B. Berde, and Timothy W. Yu. “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1644-52.

An accompanying editorial commenting on the regulatory challenges raised by personalized drugs like milasen is:

Woodcock, Janet, and Peter Marks. “Drug Regulation in the Era of Individualized Therapies.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1678-80.

When the Highly Restrictive Enrollment Criteria for Clinical Trials Steal Hope from the Innocently Desperate, It “Just Feels Unjust”

Muscular dystrophy is sometimes called “Duchenne.” The full name of the disease is “Duchenne muscular dystrophy.” When I was a student at Monroe elementary school a classmate named Frank Goldsberry played on the basketball team. In high school he was in a wheel chair with muscular dystrophy. When the high school principle, Howard Crouch, proposed to do away with the academic honor of valedictorian on the ground that there was some arbitrariness in who received it, I argued that to do would be to diminish the honor given to academic achievement. Crouch relented. It turned out that our valedictorian was Frank Goldsberry. He died a few years later in his early 20s. Frank’s father told my mother that Frank was grateful to me for speaking up. Howard Crouch had a point, but I am glad that after working hard under dire circumstances, Frank received the award.

The F.D.A. should stop mandating randomized double-blind clinical trials (RCTs) so that those who have muscular dystrophy can seek any therapy that they, their parents, and their physicians believe has promise. Not everyone will be cured, but we will learn what works through a Bayesian process of trial and error. More parents and boys will be allowed to hold on to hope.

(p. D1) Lucas was 5 before his parents, Bill and Marci Barton of Grand Haven, Mich., finally got an explanation for his difficulties standing up or climbing stairs. The diagnosis: muscular dystrophy.

Mr. Barton turned to Google.

“The first thing I read was, ‘no cure, in a wheelchair in their teens, pass in their 20s,” Mr. Barton said. “I stopped. I couldn’t read any more. I couldn’t handle it.”

Then he found a reason to hope. For the first time ever, there are clinical trials — nearly two dozen — testing treatments that might actually stop the disease.

The problem, as Mr. Barton soon discovered, is that the enrollment criteria are so restrictive that very few children qualify. As a result, families like the Bartons often are turned away.

. . .

Ryan and Brooke Saalman know how hard it can be to know what to do. “We did a lot of praying,” said Ms. Saalman, mother of two boys with Duchenne in Columbus, Ga.

They decided to enroll their oldest son, Jacob, 6, in a trial of a highly experimental drug.

. . .

. . . they discovered that gene therapy may be irreversible. And if it didn’t work, Ja-(p. D3)cob would be ineligible for an even more promising approach in the future: gene editing, to snip out the deadly mutation that causes Duchenne, an effort now in preclinical development.

. . .

The Bartons found out about a gene-therapy trial at Nationwide Children’s Hospital in Columbus, Ohio, testing a treatment by Sarepta Therapeutics.

They watched a miraculous video of a little boy struggling to walk up a flight of stairs before treatment — and then doing it easily afterward.

“This was what we were hoping for,” Mr. Barton said.

Lucas was the right age, and he seemed to qualify. But testing showed that he carries antibodies to the virus used to deliver the treatment. It would not work for him.

The Bartons were drained, devastated. And for now, there is no other trial that Lucas qualifies for.

“I had my put my hopes into this,” Mr. Barton said. “It was the miracle.”

Dr. Jeffrey Bigelow, a neurologist, and his wife, Alexis Bigelow, of Millcreek, Utah, hoped against hope that their son Henri, 8, would qualify for the only gene therapy trial that will accept boys his age.

Then the Bigelows found out that enrollees of Henri’s age have to be able to lie down and then stand up with their hands at their sides in less than 10 seconds.

It took Henri 10 seconds to do that last spring, when he was evaluated for another trial. Now it would probably take him 20 seconds, his father said.

“It feels like Henri is being punished for losing the ability to stand up from the ground too soon,” Dr. Bigelow said.

He also worries about older boys with Duchenne who are lucky enough to still walk. They are shut out from the trial because they are not yet in wheelchairs. And other trials won’t accept boys that old.

“These are boys who, like Henri, desperately need the treatment, and if they don’t get it in the next one to two years, likely will be confined to a wheelchair, to never walk again,” Dr. Bigelow said.

“This just feels unjust.”

For the full story see:

Gina Kolata. “One Shot To Qualify For Hope.” The New York Times (Tuesday, March 26, 2019 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date March 25, 2019 [sic], and has the title “For Many Boys With Duchenne Muscular Dystrophy, Bright Hope Lies Just Beyond Reach.”)

Rigid Guidelines Don’t Allow for Individualizing Treatment and Discount the Doctor’s Clinical Judgment

The criticism of the Clovers sepsis clinical trial is that the the treatment and placebo arms of the trial each require rigid adherence to a protocol, and such adherence rules out personalizing individual treatment based on individual differences among patients and doctors’ clinical judgment based on past experiences. That criticism seems plausible and also seems to apply, not just to the Clovers sepsis clinical trial, but to all< randomized double-blind clinical trials.

(p. D1) A large government trial comparing treatments for a life-threatening condition called sepsis is putting participants at risk of organ failure and even death, critics charge, and should be immediately shut down.

A detailed analysis of the trial design prepared by senior investigators at the National Institutes of Health Clinical Center in Bethesda, Md., concluded that the study “places seriously ill patients at risk without the possibility of gaining information that can provide benefits either to the subjects or to future patients.”

In a letter to the federal Office for Human Research Protection, representatives of Public Citizen’s Health Research Group compared the study, called Clovers, to “an experiment that would be conducted on laboratory animals.”

“The human subjects of the Clovers trial, as designed and currently conducted, are unwitting guinea pigs in a physiology experiment,” Dr. Michael Carome and Dr. Sidney M. Wolfe wrote in their letter.

Begun in March, Clovers is funded by the N.I.H. — despite the criticism of its own investigators — and aims to enroll 2,320 pa-(p. D3)tients at 44 hospitals around the country.

. . .

At issue is whether patients participating in Clovers are being given treatment that deviates from usual care — so much so that lives may be endangered by the research.  . . .

When patients experience septic shock, current guidelines call for raising blood pressure by administering fluids within the first three hours of care, and then administering vasopressors within the first six hours if patients do not respond to fluids.

Vasopressors can be administered early on, during or after the infusion of fluids; a new treatment guideline for hospitals says the drugs should be started within the first hour if patients aren’t responding to intravenous fluids.

Many physicians have been critical of rigid guidelines like this one because they don’t allow for individualizing treatment and appear to discount the doctor’s clinical judgment.

Both fluids in large amounts and vasopressors can cause serious complications, but when a patient’s condition continues to deteriorate, doctors use both interventions, adjusting them depending on the severity of illness.

They generally start with fluids, which in small amounts are considered less toxic than vasopressors.

But participants in Clovers are randomly assigned to a “liberal fluids” group who receive large infusions of fluids in a very short time but limits the use of vasopressors, or to a “restrictive fluids” group in which fluids are minimized and drug treatment begun earlier.

For the full story see:

Roni Caryn Rabin. “Critics Demand Halt of a Sepsis Trial.” The New York Times (Tuesday, September 25, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Sept. 24, 2018 [sic], and has the title “Trial by Fire: Critics Demand That a Huge Sepsis Study Be Stopped.”)